Nalmefene [17-(cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol] has the following general formula:
and can be prepared using methods that are well known in the art e.g. starting by manufacturing of naltrexone from noroxymorphone as described in WO 2012/059103 and subsequently manufacturing nalmefene from naltrexone e.g. by the Wittig reaction as described in WO 2010/136039.
Nalmefene is an opioid system modulator with a distinct μ, δ, and κ receptor profile. In vitro studies have demonstrated that nalmefene is a selective opioid receptor ligand with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor. Acute alcohol intake was shown to result in mesolimbic dopamine release (facilitated by the release of β-endorphins), which can provide positive reinforcement. Nalmefene is thought to counteract the reinforcement effects and to reduce alcohol consumption, possibly by modulating these cortico-mesolimbic functions.
The efficacy and tolerability of nalmefene in the treatment of alcohol dependence have been evaluated in three phase III studies (two confirmatory 6-month efficacy studies and one 1-year safety study) conducted by Lundbeck (Mann et al. Extending the Treatment Options in Alcohol Dependence: A Randomized Controlled Study of As-Needed Nalmefene. Biol Psychiatry (2013); 73(8): 706-713; Gual et al. A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. European Neuropsychopharmacology (2013); 23(11): 1432-1442; van den Brink et al., Long-term efficacy, tolerability and safety of nalmefene as-needed in patients with alcohol dependence: A 1-year, randomised controlled study. J. Psychopharmacol., published online before print Mar. 26, 2014, doi: 1 0.1177/0269881114527362) and 5 studies in alcohol use disorders conducted by the company Biotie (Karhuvaara et al. Alcohol. Clin Exp Res. (2007); 31:1179-1187).
A marketing authorization was granted in February 2013 in the European Union (EU) for oral nalmefene under the tradename Selincro® for the reduction of alcohol consumption in adult patients with alcohol dependence.
The only known salt of nalmefene is the hydrochloride salt. Said nalmefene hydrochloride salt has been described as a hydrate-forming salt and known forms are nalmefene hydrochloride monohydrate (Brittain, H.G., Analytical Profiles of Drug Substances and Excipients; 1996, Vol. 24: 351-395) and nalmefene hydrochloride dihydrate (WO 2010/063292). Methods for obtaining said nalmefene hydrochloride monohydrate and dihydrate from crude nalmefene hydrochloride are described in WO 2010/063292.
It has not been possible to obtain a stable anhydrous form of Nalmefene hydrochloride as formation of anhydrous material by dehydration of a hydrate lead to hygroscopic material that absorbs water under transformation to a hydrate, and crystallization from ethanol lead to ethanol solvate (Brittain, H.G., Analytical Profiles of Drug Substances and Excipients; 1996, Vol. 24: 351-395 and WO 2010/063292).
There is a need for new salts of nalmefene with improved properties e.g. for chemical processing and for pharmaceutical formulation and storage.